Process for the preparation of epsilon-ketonic acids



United States Patent The invention relates to a process for thepreparation of e-ketonic acids.

The British patent specification No. 748,801 describes a number ofmethods for the preparation of e-ketonic acids:

(a) An alkyl halide, e.g. an alkyl bromide, is condensed with the aid ofe.g. magnesium with a di-ester of malonic acid, preferably the dibenzylester, to form the corresponding alkyl malonate. This ester issubsequently condensed with adipic anhydride and the reaction product ishydrogenated. The tricarboxylic acid thus obtained loses 2 molecules ofcarbon dioxide and in this way yields the e-ketonic acid.

(b) An alkyl halide, e.g. an alkyl bromide, is condensed withcycloheptane-dion-l,3, with the aid of e.g. sodium. The2-alkylcycloheptane-dion-1,3, thus obtained, when treated with alkaliand subsequently acidified, yields the e-ketonic acid.

(0) An alkyl magnesium halide, e.g. an alkyl magnesium bromide, iscondensed with an adipic alkyl imide, e.g. adipic methyl imide. Aftersaponification and acidification the condensation product gives thee-ketonic acid.

(d) An alkyl magnesium halide, e.g. an alkyl magnesium bromide, iscondensed with cyclohexanone. The alkyl cyclohexanol thus formed issubsequently dehydrated with e.g. acid potassium sulphate, upon whichthe alkyl cyclohexene thus obtained gives the e-ketonic acid throughoxidation with e.g. chromic acid.

(e) A zinc or cadmium dialkyl is condensed with an acid halide,preferably the acid chloride, of an adipic mono-ester, e.g. the methylester. The e-ketonic ester thus formed is converted by saponificationand acidification into the corresponding e-kBiOlllC acid.

(7) A Z-alkyl cyclohexanone, to be prepared by condensation ofcyclohexanone with an aliphatic aldehyde, followed by dehydration andhydrogenation, is oxidized with chromic acid. From the latter ae-ketonic acid is formed directly.

All these methods of preparation involve drawbacks.

In the methods a and b an alkyl halide has to be prepared from acorresponding carboXylic acid, which is rather a laborious process; thepreparation of an acid halide from the acid is much simpler.

In the methods 0, d, and e the same drawback applies as for a and b.Since in these cases the condensation moreover takes place via a metalcompound, the latter can contain no substituent the presence of whichmakes the preparation of the said metal compound impossible. Furthermoreconsiderable precautions are required in operating on a large scale.

In method finally the difficulty of access of the compound to beoxidized is a considerable drawback.

In the methods for the lengthening of the chain of acid halides to forme-ketonic acids, as mentioned in the literature (Chem. Rev. 57, 209-14(1957) and Dutch patent application No. 188,921 (1954)), it is statedthat the process may start from a substituted malonic or acylaceticester with the general formula:

in which R stands for an alkyl radical, R for an alkyl or aryl radical,and A for a group which after saponification may be converted into acarboxyl group.

Acylation with an acid halide, preferably an acid chloride followed bysaponification and decarboxylation, and splitting otf of the smallestacyl group respectively, is said to give the desired e-ketonic acid.However, it is rather curious that no actual example for the preparationof a e-ketonic acid is to be found in the literature.

In Chem. Listy 49, 1940-3 (1955) a method is described according towhich e-ketonic acids are prepared by the condensation of acid chlorideswith 2-ketocyclopentane carboxylic ethyl ester. To this end thebromomagnesium compound of Z-ketocyclopentane carboxylic ethyl ester isprepared, which is subsequently acylated with the acid chloride inquestion. Although the 2-ketocyclopentane carboxylic ethyl ester is muchmore easily accessible than a substituted malonic or acetylacetic ester,the preparation of and the manipulation with the Grignard compound giverise to difficulties when the process is carried out on a large scale. a1

Now it was surprisingly found that instead of the Grignard compound analkali derivative of a 2-ketocyclopentane carboxylic ester can beacylated with an acid halide in a strikingly simple way.

Accordingly e-ketonic acids are prepared according to the invention insuch a way that an adipic dialkyl ester, after Dieckmann condensationwith the aid of an alkali metal, is reacted with an acid halide havingthe formula RCOX, in which R represents an aliphatic substituted ornon-substituted branched or non-branched radical and X a halogen atom,followed by saponification, opening of the ring, decarboxylation, andacidification.

The process according to the invention is as follows: Substituted ornon-substituted branched or non-branched carboxylic acids are condensedvia the corresponding acid halides in an inert solvent, preferablytoluene, with an adipic dialkyl ester, after the latter has beenconverted through Dieckmann condensation with the aid of an alkalimetal, preferably sodium or potassium, into the alkali compounds with a2-keto-cyclopentane carboxylic ester. After the conventionalsaponification, opening of the ring, and decarboxylation, followed byacidification, the e-kctonic acid is obtained. This method results in alengthen-' ing of the chainby five carbon atoms.

The process according to the invention thus avoids the preparation ofand the manipulation with the Grignard compound, in consequence of whichthe dangerous reaction medium ether is avoided at the same time.Furthermore it has to be considered very striking that the2-ketocyclopentane carboxyli'c ester need not be prepared separately. Infact, the process may start from an adipic dialkyl ester, which afterDieckmann condensation is reacted directly with the acid halide inquestion. The process is carried out in an inert solvent and the alcoholthus formed is preferably distilled off simultaneously,"

upon which the acid halide is added to the reaction 3 mixture. In thisway the desired e-ketonic acid is obtained from the acid halide and theadipic dialkyl ester in one continuous series of operations. From thetechnical point of view therefore this amounts to an incredibly simplemethod of carrying out the process in question.

The two alkyl radicals of the adipic ester may be branched ornon-branched saturated hydrocarbon radicals.

The acid halide preferably used is the chloride or the bromide.

The process according to the invention presents the possibility ofgreatly simplifying the synthesis of e.g. many macrocyclic compoundsapplied as scenting agents. Indeed, to this end the acid halide is sochosen that it contains a preferably terminal reactive substituent,which may or may not be protected, e.g. a protected hydroxyl group, aprotected carboxyl group, a halogen atom, a double bond. Thuspentadecanolide, for example, may be prepared by starting fromIO-acetoxydecanoyl chloride, upon which the 15-hydroxy6-ketopentadecanoic acid obtained by the above method is reducedaccording to Wollf-Kishner and then lactonized. In a similar wayhexadecanolide may be prepared from ll-bromo-undecanoyl chloride.Undecen-lO-oyl chloride yields 6-ketohexadecenicl-acid. Furthermorecyclopentadecanone, for example, may be prepared by starting from9-ethoxycarbonyl nonanoyl chloride. In this case the last steps are anacyloine ring closure with subsequent reduction.

EXAMPLE I Preparation of 6-ket0hexadecenic-15-acid To a suspension of 25g. (1 mole) of finely divided sodium in 1000 g. of toluene, 2 g. ofabsolute ethanol and 202 g. (1 mole) of adipic diethyl ester aresuccessively added in drops. The mixture is then boiled with vigorousstirring, a gradual Dieckmann condensation taking place and the ethanolthus formed being distilled off azeotropically.

When the reaction is complete after about 3 hours, at 0 C. 223 g. (1.1moles) of undecen--oyl chloride is added in drops and the reactionmixture is stirred for 4 hours, the temperature being gradually raisedto 50 C. during the first two hours. The reaction mixture issubsequently poured out into 500 ml. of ice-water, the toluene layer isseparated off, and the latter is evaporated under reduced pressure. Theresidue is now boiled for 14 hours with a solution of 127 g. (1.2 moles)of sodium carbonate in 1500 g. of water. After being cooled, the mixtureis acidified, Congo red being used as indicator, and the crude acid isrecrystallized from petroleum ether. The product obtained is 171 g. of6-ketohexadecenic-15- acid with melting point 6869 C. Yield 64% of thetheory, referred to the reacted adipic diethyl ester.

From the mother liquor it is possible to recover through distillation 72g. (0.39 mole) of undecenic acid, from which with the aid of thionylchloride the corresponding acid chloride can be prepared again in ayield of 91% of the theory. In consequence, the yields of e-ketonicacid, referred to the acid chloride, becomes 86% of the theory.

EXAMPLE II Preparation of d-ketononanoic acid In accordance with ExampleI, 39 g. (1 mole) of potassium is reacted with 202 g. (1 mole) of adipicdiethyl ester, and the potassium salt of Z-ketocyclopentane carboxylicethyl ester thus formed is condensed with 117 g. (1.1 moles) of butyricchloride. The reaction product is worked up again in accordance withExample I and subsequently boiled for 12 hours with a solution of 166 g.(1.2 moles) of potassium carbonate in 1000 g. of water. After beingcooled and acidified, the crude acid is distilled and the product thusobtained is 75 g. of 6-ketononanoicacid with boiling point ISO-153 C. at4mm.

4 I mercury pressure and melting point 37-38 C. Yield 44% of the theory.

EXAMPLE HI Preparation of 8-methyl 6-ket0nonan0ic acid In accordancewith Example I, from 11.5 g. (0.5 mole) of sodium and 101 g. (0.5 mole)of adipic diethyl ester the B-ketonic ester is prepared and the latteris subsequently condensed with 91 g. (0.55 mole) of isovaleric bromide.After being worked up according to the abovementioned process, the crudecondensation product is boiled for 12 hours with a solution of 64 g.(0.6 mole) of sodium carbonate in 500 g. of water. Through acidificationthere is obtained: 87 g. of S-methyl 6-ketononanoic acid with boilingpoint 164-166" C. at 6 mm. mercury pressure and melting point 39-40 C.Yield 47% of the theory.

EXAMPLE IV Preparation of 6-ket0tricosanoic acid In accordance withExample I, 23 g. (1 mole) of sodium is reacted with 202 g. (1 mole) ofadipic diethyl ester, and the reaction product is condensed with 313 g.(1.1 moles) of stearoyl chloride. After the conventional working-up thecondensation product is boiled for 14 hours with a solution of 159 g.(1.5 moles) of sodium carbonate in 1500 g. of water. Cooling,acidification, and recrystallization of the crude acid from petroleumether yields: 238 g. of 6-ketotricosanoic acid with melting point101-102 C. Yield 65% of the theory.

EXAMPLE V Preparation of IS-hydroxy 6-ketopenladecan0ic acid Inaccordance with Example I, 11.5 g. (0.5 mole) of sodium is reacted with101 g. (0.5 mole) of adipic diethyl ester and the reaction product iscondensed with 127 g. (0.51 mole) of 10-acet0xydecanoyl chloride. Thecorn densation product thus formed is worked up and subsequently boiledfor 16 hours with a solution of g. (1.6 moles) of potassium hydroxide ina mixture of 600 g. of water and 300 g. of methanol.

After being cooled, the mixture is diluted with 400 g. of water andacidified, and the crude mixture of 15-hydroxy 6-ketopentadecanoic acidand 10-hydroxydecanoic acid thus obtained is separated. This gives: 82g. of 15- hydroxy 6-ketopentadecanoic acid with melting point 87- 88 C.Yield 60% of the theory. A quantity of 26 g. (0.14 mole) of10-hydroxydecanoic acid may be recovered.

EXAMPLE VI Preparation of 16-hydr0xy 6-ket0hexadecanoic acid Inaccordance with Example I, the sodium compound of 2-ketocyclopentanecarboxylic ethyl ester prepared from 11.5 g. (0.5 mole) of sodium and101 g. (0.5 mole) of adipic diethyl ester is condensed with g. (0.51mole) of ll-bromo-undecanoyl chloride. After being Worked up, thecondensation product is boiled for 16 hours with a solution of 64 g.(1.6 moles) of sodium hydroxide in 1000 g. of Water. The clear solutionis cooled and acidified, Congo red being used as indicator, upon whichthe crude mixture of 16-hydroxy 6-ketohexadecanoic acid and ll-hydroxyundecanoic acid thus obtained is separated. In this way the productobtained is: 76 g. of 16-hydroxy 6-ketohexadecanoic acid With meltingpoint 9192 C. Yield 53% of the theory. In addition 22 g. (0.11 mole) ofll-hydroxy undecanoic acid may be recovered.

EXAMPLE VII Preparation of 5-ket0tetradecane-dicarboxyIic acid-1.14

In accordance with Example I, 7.8 g. (0.2 mole) of potassium is reactedwith 40.4 g. (0.2 mole) of adipic di ethyl ester, and the cyclic ketonicester thus formed is condensed with 50 g. (0.2 mole) of9-ethoxycarbonylnonanoyl chloride. Working-up and boiling for 16 hourswith a solution of 28 g. (0.7 mole) of sodium hydroxide in a mixture of300 g. of Water and 100 g. of ethanol yields, after acidification, amixture of S-ketotetradecanedicanboxylic acid-1.14 and sebacic acid.From this mixture there is Obtained, after separation: 27 g. ofS-ketotetradecane-dicarboxylic acid-1.14 with melting point 108- 109 C.Yield 48% of the theory.

A quantity of 14 g. (0.07 mole) of sebacic acid may be recovered.

What we claim is:

1. A process for the preparation of e-ketonic acids comprising reactingan alkali metal derivative of a 2-ketocyclopentane-carboxylic loweralkyl ester with an acid halide having the formula RCOX in which R is analkyl radical selected from the group consisting of branched andnon-branched alkyl radicals having at most 17 carbon atoms and in whichX is a halogen atom, subjecting the reaction mixture to boiling with abasic solution selected from the group of alcoholic and aqueous basicsolutions, and then acidification.

2. A process according to claim 1 in which the alkyl radical representedby R is further selected from the group consisting of an alkyl radicalcontaining an olefinic bond, an alkyl radical containing a halogen atom,an alkyl radical containing an ester group, and an alkyl radicalcontaining a protected hydroxyl group.

3. A process for the production of e-ketonic acids, which comprisesconverting a lower dialkyl ester of adipic acid by Dieckmanncondensation with the aid of an alkali metal into the alkali metalderivative of a 2-keto-cyclopentane carboxylic alkyl ester, reacting thesaid metal derivative with an acid halide having the formula RCOX inwhich R is an alkyl radical selected from the group consisting ofbranched and non-branched alkyl radicals having at most 17 carbon atomsand in which X is a halogen atom, subjecting the reaction mixture toboiling with a basic solution selected from the group of alcoholic andaqueous basic solutions, and then acidification.

4. A process according to claim 3 in which the alkyl radical representedby R is further selected from the group consisting of an alkyl radicalcontaining an olefinic bond, an alkyl radical containing a halogen atom,an alkyl radical containing an ester group, and an alkyl radicalcontaining a protected hydroxyl group.

5. A process according to claim 3, in which in one reaction vessel theadipic dialkyl ester is subjected, in an inert solvent, to the Dieckmanncondensation with the aid of its alkali metal, the alcohol formed beingdistilled off simultaneously, and the acid halide is subsequently addedto the reaction mixture.

6. A process according to claim 3, in which the lower dialkyl ester ofadipic acid is the diethyl ester.

7. A process according to claim 3, in which the alkali metal is sodium.

8. A process according to claim 3, in which the alkali metal ispotassium.

9. A process according to claim 3, in which the acid halide is an acidchloride.

10. A process according to claim 3, in which the acid halide is an acidbromide.

11. A process according to claim 3, in Which the acid halide is stearoylchloride.

12. A process according to claim 3, in which the acid halide isundecen-lO-oyl chloride.

13. A process according to claim 3, in which the acid halide isll-bromo-undecanoyl chloride.

14. A process according to claim 3, in which the acid halide is9-ethoxycarbonyl-nonanoyl chloride.

15. A process according to claim 3, in which the acid halide isl0-acetoxy-decanoyl chloride.

16. A process according to claim 3, in which the acid halide isvalereanoyl bromide.

17. A process for the preparation of a e-ketonic acid comprisingreacting adipic diethyl ester with an alkali metal selected from thegroup consisting of sodium and potassium to efiect a Dieckmanncondensation, condensing the reaction product with an acid halideselected from the group consisting of butyric chloride, isovalericbromide, stearoyl chloride, undecen-lO-oyl chloride, 10-acetoxy-decanoylchloride, ll-bromo-undecanoyl chloride, and 9-ethoxycarbony1 chloride,subjecting the reaction product to boiling with a basic solutionselected from the group of alcoholic and aqueous basic solutions, andthen acidification.

No references cited.

1. A PROCESS FOR THE PREPARATION OF E-KETONIC ACIDS COMPRISING REACTINGAN ALKALI METAL DERIVATIVE OF A 2-KETOCYCLOPENTANE-CARBOXYLIC LOWERALKYL ESTER WITH AN ACID HALIDE HAVING THE FORMULA RCOX IN WHICH R IS ANALKYL RADICAL SELECTED FROM THE GROUP CONSISTING OF BRANCHED ANDNON-BRANCHED ALKYL RADICALS HAVING AT MOST 17 CARBON ATOMS AND IN WHICHX IS A HALOGEN ATOM, SUBJECTING THE REACTION MIXTURE TO BOILING WITH ABASIC SOLUTION SELECTED FROM THE GROUP OF ALCOHOLIC AND AQUEOUS BASICSOLUTIONS, AND THEN ACIDIFICATION.